Variability of oxygenation in possible hepatopulmonary syndrome: effects of requiring two abnormal arterial blood gas results for diagnosis.

BACKGROUND AND AIMS: Hepatopulmonary syndrome (HPS) affects 10-32 % of patients with cirrhosis and is defined by liver abnormalities, intrapulmonary vascular dilatations (IPVDs), and abnormal oxygenation. However, published criteria for abnormal oxygenation are inconsistent. We sought to evaluate variation in oxygenation over time and to compare various diagnostic criteria for validity, based on their diagnostic stability over time and ability to identify patients with clinically relevant findings. METHODS: We retrospectively analyzed oxygenation and diffusion capacity in patients with liver abnormalities and IPVDs who had ≥ 2 arterial blood gases (ABGs) at the University of Toronto or Universite de Montreal. We compared the performance of nine possible oxygenation criteria for HPS and for each explored whether validity improved when requiring two consecutive abnormal ABGs on different days. RESULTS: Mean PaO2 was 68.4 mmHg and annual within-patient coefficient of variation 6.3 % (58 patients). Applying published criteria, 8.6-15.5 % of patients initially diagnosed with HPS no longer met the criterion for HPS on a subsequent ABG (re-classified). Requiring two consecutive abnormal ABGs on different days: (1) reduced the proportion of re-classified patients (9/9 criteria); (2) identified patients with more rapid progression in hypoxemia and greater difference in rate of progression between HPS and non-HPS (7/9 criteria); and (3) identified patients with lower diffusion and a larger difference in diffusion between HPS and non-HPS (8/9 criteria). CONCLUSIONS: Oxygenation is variable in this population, and requiring two abnormal results might reduce misdiagnosis and better differentiate patients with and without HPS according to clinically relevant markers of disease.

Impact of cytolysis following transarterial chemoembolization for hepatocellular carcinoma.

BACKGROUND AIMS: Transarterial chemoembolization (TACE) is increasingly used as a treatment of hepatocellular carcinoma. Cytolysis, which may occur within days following the procedure is due to either necrosis of the tumour or of the non-tumoral parenchyma. Therefore it may influence either tumour response or liver function or both. We evaluated the impact of cytolysis after TACE on tumour response, incidence of hepatobiliary complications and overall survival. METHODS: We conducted a retrospective analysis of 157 patients with liver disease who underwent 271 treatments for hepatocellular carcinoma. Cytolysis was defined as an increase of AST value above 100 IU/L with at least doubling of the baseline value. The associations between cytolysis and radiologic tumor response two months following each treatment and adverse hepatobiliary events were estimated using generalized estimating equations models. Comparison of 18 months survival after a first treatment of chemoembolization between the groups with and without cytolysis was performed using the proportional hazards model. RESULTS: Cytolysis occurred in 198 out of 271 cases and was associated with a favourable radiological response (OR 1.90, 1.03-3.54) at two months compared to non-cytolysis with no difference in the occurrence of adverse hepatobiliary events. The adjusted hazard ratio for overall survival was 1.33 times greater in the group with cytolysis compared to non-cytolysis (0.45-3.90). CONCLUSIONS: The occurrence of cytolysis was associated with a favorable radiological response, but had no impact on short-term adverse events and on survival at 18 months.

The Fatty Liver Index has limited utility for the detection and quantification of hepatic steatosis in obese patients.

PURPOSE: Noninvasive tools for the detection of hepatic steatosis are needed. The Fatty Liver Index (FLI), which includes body mass index (BMI), waist circumference, triglycerides, and γ-glutamyl-transferase, has been proposed as a screening tool for fatty liver. Our objective was to validate the FLI for the detection and quantification of hepatic steatosis in an obese population. METHODS: Patients with chronic liver disease and BMI ≥ 28 kg/m(2) underwent liver biopsy and FLI determination. FLI performance for diagnosing steatosis compared with biopsy was assessed using areas under receiver operating characteristic curves (AUROCs), and a novel model for the prediction of significant steatosis (≥5 %) was derived. RESULTS: Among 250 included patients, 65 % were male, and the median BMI was 33 kg/m(2); 48 % had nonalcoholic fatty liver disease, and 77 % had significant (≥5 %) steatosis. The FLI was weakly correlated with the percentage (ρ = 0.25, p = 0.0001) and grade of steatosis (ρ = 0.28, p < 0.00005). The median FLI was higher among patients with significant steatosis (91 vs. 80 with <5 % steatosis; p = 0.0001) and the AUROC for this outcome was 0.67 (95 % CI 0.59-0.76). At an optimal FLI cut-off of 79, the FLI was 81 % sensitive and 49 % specific, and had positive and negative predictive values of 84 and 43 %, respectively. A novel index including triglycerides, glucose, alkaline phosphatase, and BMI outperformed the FLI for predicting significant steatosis [AUROCs 0.78 vs. 0.68; p = 0.009 (n = 247)]. CONCLUSIONS: In obese patients, the FLI is a poor predictor of significant steatosis and has limited utility for steatosis quantification compared with liver histology. A novel index including triglycerides, glucose, alkaline phosphatase, and BMI may be useful, but requires validation.

Direct comparison of the FibroScan XL and M probes for assessment of liver fibrosis in obese and nonobese patients.

BACKGROUND: A novel Fibroscan XL probe has recently been introduced and validated for obese patients, and has a diagnostic accuracy comparable with that of the standard M probe. The aim of this study was to analyze and understand the differences between these two probes in nonobese patients, to identify underlying causes for these differences, and to develop a practical algorithm to translate results for the XL probe to those for the M probe. METHODS AND RESULTS: Both probes were directly compared first in copolymer phantoms of varying stiffness (4.8, 11, and 40 kPa) and then in 371 obese and nonobese patients (body mass index, range 17.2-72.4) from German (n = 129) and Canadian (n = 242) centers. Liver stiffness values for both probes correlated better in phantoms than in patients (r = 0.98 versus 0.82, P < 0.001). Significantly more patients could be measured successfully using the XL probe than the M probe (98.4% versus 85.2%, respectively, P < 0.001) while the M probe produced a smaller interquartile range (21% versus 32%). Failure of the M probe to measure liver stiffness was not only observed in patients with a high body mass index and long skin-liver capsule distance but also in some nonobese patients (n = 10) due to quenching of the signal from subcutaneous fat tissue. In contrast with the phantoms, the XL probe consistently produced approximately 20% lower liver stiffness values in humans compared with the M probe. A long skin-liver capsule distance and a high degree of steatosis were responsible for this discordance. Adjustment of cutoff values for the XL probe (<5.5, 5.5-7, 7-10, and >10 kPa for F0, F1-2, F3, and F4 fibrosis, respectively) significantly improved agreement between the two probes from r = 0.655 to 0.679. CONCLUSION: Liver stiffness can be measured in significantly more obese and nonobese patients using the XL probe than the M probe. However, the XL probe is less accurate and adjusted cutoff values are required.

The transjugular intrahepatic portosystemic shunt in the treatment of portal hypertension: current status.

The transjugular intrahepatic portosystemic shunt (TIPS) represents a major advance in the treatment of complications of portal hypertension. Technical improvements and increased experience over the past 24 years led to improved clinical results and a better definition of the indications for TIPS. Randomized clinical trials indicate that the TIPS procedure is not a first-line therapy for variceal bleeding, but can be used when medical treatment fails, both in the acute situation or to prevent variceal rebleeding. The role of TIPS to treat refractory ascites is probably more justified to improve the quality of life rather than to improve survival, except for patients with preserved liver function. It can be helpful for hepatic hydrothorax and can reverse hepatorenal syndrome in selected cases. It is a good treatment for Budd Chiari syndrome uncontrollable by medical treatment. Careful selection of patients is mandatory before TIPS, and clinical followup is essential to detect and treat complications that may result from TIPS stenosis (which can be prevented by using covered stents) and chronic encephalopathy (which may in severe cases justify reduction or occlusion of the shunt). A multidisciplinary approach, including the resources for liver transplantation, is always required to treat these patients.

Hepatic hemodynamics in 24 patients with nodular regenerative hyperplasia and symptomatic portal hypertension.

BACKGROUND AND AIM: To evaluate hepatic hemodynamics in patients with nodular regenerative hyperplasia of the liver (NRH) with portal hypertension (PHT). METHODS: We retrospectively reviewed the charts of 24 patients referred for PHT related to biopsy-proven NRH. Hemodynamic measurements included wedged hepatic vein (WHVP) and inferior vena cava (IVCP), and, in 12 patients, portal vein pressure (PVP). Hepatic vein pressure gradient (HVPG: WHVP-IVCP) and portal vein pressure gradient (PVPG: PVP-IVCP) were calculated. RESULTS: Nodular regenerative hyperplasia was associated in 24 patients with various diseases (oxaliplatin chemotherapy, treatment with purine antagonists, post liver transplantation, hematologic and rheumatologic conditions and HIV infection). Liver function parameters were either completely normal or slightly impaired. Patients were referred for gastroesophageal varices (n = 18), and/or ascites (n = 11), and/or splenomegaly (n = 20). In patients with varices or ascites, HVPG was lower than 10 mmHg (a cut-off point for the presence of varices and/or ascites) in 15/21, suggesting a pre-sinusoidal component to their PHT confirmed by a PVP higher than 12 mmHg in 12/12 patients. The mean difference between HVPG and PVPG was 8.7 mmHg in these patients. Ten patients were treated by transjugular intrahepatic portosystemic shunt. None of them re-bled, and one presented transient hepatic encephalopathy. CONCLUSIONS: Presinusoidal PHT associated with NRH is probably related to compression of portal venules by the regenerative nodules. In patients with HTP and a HVPG < 10 mmHg, the diagnosis of NRH must be suspected and PVP measured, which is important in the management of these patients.

Controlled Attenuation Parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography.

BACKGROUND: Accurate tools for the noninvasive detection of hepatic steatosis are needed. The Controlled Attenuation Parameter (CAP) specifically targets liver steatosis using a process based on transient elastography. METHODS: Patients with chronic liver disease and body mass index (BMI) ≥28 kg/m(2) underwent biopsy and liver stiffness measurement (LSM) with simultaneous CAP determination using the FibroScan(®) M probe. The performance of the CAP for diagnosing steatosis compared with biopsy was assessed using areas under receiver operating characteristic curves (AUROC). RESULTS: A total of 153 patients were included: 69% were male, median BMI was 32 kg/m(2); 47% had nonalcoholic fatty liver disease (NAFLD); and 65% had significant (≥10%) steatosis. The CAP was significantly correlated with the percentage of steatosis (ρ = 0.47) and steatosis grade (ρ = 0.51; both P < 0.00005). The median CAP was higher among patients with significant steatosis (317 [IQR 284-339] vs. 250 [227-279] dB/m with <10% steatosis; P < 0.0005) and the AUROC for this outcome was 0.81 (95% CI 0.74-0.88). At a cut-off of 283 dB/m, the CAP was 76% sensitive, 79% specific, and had positive and negative predictive values of 87% and 64%, respectively. CAP performance was not influenced by measurement variability, but was higher in patients with mild (F0-F1) fibrosis (AUROC 0.89 vs. 0.72 with F2-F4; P = 0.03). The AUROCs of the CAP for ≥5%, >33% and >66% steatosis were 0.79, 0.76 and 0.70, respectively. CONCLUSIONS: The CAP is a promising tool for the noninvasive detection of hepatic steatosis. Advantages of CAP include its ease of measurement, operator-independence and simultaneous availability with LSM for fibrosis assessment.

Feasibility and diagnostic performance of the FibroScan XL probe for liver stiffness measurement in overweight and obese patients.

UNLABELLED: Failure of liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) and unreliable results occur in ≈ 5% and 15% of patients, respectively, mainly due to obesity. In this multicenter study, we evaluated the feasibility and performance of the novel FibroScan XL probe in 276 patients with chronic liver disease (42% viral hepatitis, 46% nonalcoholic fatty liver disease [NAFLD]) and a body mass index (BMI) ≥ 28 kg/m(2) . Patients underwent liver biopsy and TE with the standard M and XL probes. TE failure was defined as no valid LSMs and unreliable examinations as <10 valid LSMs or an interquartile range (IQR)/LSM >30% or success rate <60%. Probe performance for diagnosing ≥ F2 fibrosis and cirrhosis (F4) versus biopsy were examined using areas under receiver operating characteristic curves (AUROC). FibroScan failure was less frequent with the XL probe than the M probe (1.1% versus 16%) and the XL probe was more often reliable (73% versus 50%; both P < 0.00005). Reliable results with the XL probe were obtained in 61% of patients in whom the M probe was unreliable. Among 178 patients with ≥ 10 valid LSMs using both probes, liver stiffness was highly correlated between probes (ρ = 0.86; P < 0.0005); however, median liver stiffness was lower using the XL probe (6.8 versus 7.8 kPa; P < 0.00005). The AUROC of the XL and M probes were similar for ≥ F2 fibrosis (0.83 versus 0.86; P = 0.19) and cirrhosis (0.94 versus 0.91; P = 0.28). CONCLUSION: Compared with the M probe, the FibroScan XL probe reduces TE failure and facilitates reliable LSM in obese patients. Although the probes have comparable accuracy, lower liver stiffness cutoffs will be necessary when the XL probe is used to noninvasively assess liver fibrosis.

Discordance in fibrosis staging between liver biopsy and transient elastography using the FibroScan XL probe.

BACKGROUND & AIMS: The FibroScan XL probe facilitates liver stiffness measurement (LSM) by transient elastography (TE) in obese patients, yet factors affecting its accuracy have not been described. Our objectives were to examine the prevalence, risk factors, and causes of discordance between fibrosis estimated by the FibroScan XL probe and biopsy. METHODS: Two hundred and ten patients with chronic liver disease (45% viral hepatitis, 55% nonalcoholic fatty liver disease (NAFLD) and a body mass index (BMI) ≥ 28 kg/m(2)) underwent liver biopsy and TE with the FibroScan XL probe. Predictors of discordance ≥ 2 fibrosis stages between measures, which occurred in 11% of patients (n=24), were identified by comparing patient, TE, and biopsy characteristics of discordant and non-discordant cases. RESULTS: Fibrosis estimated by the FibroScan XL probe was greater than biopsy in 75% (18/24) of discordant cases. Although biopsy quality was not associated with discordance, discordant cases were less likely to have ≥ 10 valid shots (75% vs. 97%; p=0.001), a success rate ≥ 60% (67% vs. 95%; p <0.0005), and an interquartile range over median liver stiffness (IQR/M) <21% (37% vs. 57%; p=0.07) than non-discordant cases. However, only increased BMI (odds ratio [OR] 1.09 per kg/m(2); 95% confidence interval [CI] 1.01-1.18; p=0.04) was independently associated with discordance; liver stiffness was of borderline significance (OR 1.73 per log(10)-transformed value; 95% CI 0.95-3.18; p=0.08). Discordance was 4- to 5-fold more frequent among patients with severe obesity (BMI ≥ 40 kg/m(2): 32% vs. 8%) and liver stiffness above the median of 7.0 kPa (20% vs. 4%; both p <0.0005). CONCLUSIONS: Discordance between liver fibrosis estimated by biopsy and TE using the FibroScan XL probe was infrequent in this obese population. Patients with severe obesity and elevated liver stiffness have the greatest risk of discordance.

Usefulness of endoscopic ultrasonography in hepatology.

Endoscopic ultrasonography (EUS) is used to evaluate patients with hepatobiliary diseases. The technique is useful for the diagnosis of esogastric varices in selected cases of portal hypertension, and to evaluate the pathogenic role and prognostic value of the collateral circulation in patients with this condition. When coupled with the Doppler technique, EUS can be used to guide injection sclerotherapy and to verify the obliteration of varices (particularly fundal varices) after endoscopic treatment. Hemodynamic changes induced in the collateral circulation by vasoactive drugs can also be measured with Doppler-EUS. Fine-needle aspiration under EUS guidance is useful in the diagnosis of focal liver lesions and perihepatic adenopathy, and in the evaluation of biliary tract diseases. New indications can be developed in the future after adequate experimental validation.

Transcatheter arterial chemoembolization of hepatocellular carcinoma as a bridge to liver transplantation: a retrospective study.

Background. Transcatheter arterial lipiodol chemoembolization (TACE) can be used in cirrhotic patients with hepatocellular carcinoma to avoid tumor progression before transplantation. Objective. To evaluate the efficacy and safety of TACE used as a bridge to liver transplantation. Methods. TACE was performed in 30 cirrhotic patients with hepatocellular carcinoma. Milan criteria were used to select patients for transplant. Patients had a good or moderately impaired liver function, no arterioportal fistulae, and a good portal perfusion. Results. 48 TACE were performed in 30 patients. Before transplantation, 4 patients were dropped off the list due to tumor extension or liver failure. Complete necrosis of the tumor was observed in 11 patients and partial necrosis in 15 patients. After transplantation, 6 patients died and tumor recurrence was observed in 5 patients with a tumor beyond Milan criteria or no response to TACE. Conclusion. TACE is useful as a bridge to liver transplantation in a selected group of cirrhotic patients with hepatocellular carcinoma. A combined therapeutic approach before surgery might improve the prognosis in these patients.

Transient elastography for the noninvasive assessment of liver fibrosis: a multicentre Canadian study.

BACKGROUND: Liver stiffness measurement (LSM) using transient elastography (TE) is a promising tool for the noninvasive assessment of hepatic fibrosis. OBJECTIVES: To determine the feasibility and performance of TE in a North American cohort of patients with chronic liver disease. METHODS: LSMs were obtained using TE in 260 patients with chronic hepatitis B or C, or nonalcoholic fatty liver disease from four Canadian hepatology centres. The accuracy of TE compared with liver biopsy for the prediction of significant fibrosis (Metavir fibrosis score of F2 or greater), bridging fibrosis (Metavir fibrosis score of F3 or greater) and cirrhosis (Metavir fibrosis score of F4 ) was assessed using area under ROC curves (AUROCs), and compared with the aspartate aminotransferase-to-platelet ratio index. The influence of alanine aminotransferase (ALT) levels and other factors on liver stiffness was determined using linear regression analyses. RESULTS: failure of TE occurred in 2.7% of patients, while liver biopsies were inadequate for staging in 0.8%. Among the remaining 251 patients, the AUROCs of TE for Metavir fibrosis scores of F2 and F3 or greater, and F4 were 0.74 (95% CI 0.68 to 0.80), 0.89 (95% CI 0.84 to 0.94), and 0.94 (95% CI 0.90 to 0.97), respectively. LSM was more accurate than the aminotransferase-to-platelet ratio index for bridging fibrosis (AUROC 0.78) and cirrhosis (AUROC 0.88), but not significant fibrosis (AUROC 0.76). At a cut-off of 11.1 kPa, the sensitivity, specificity, and positive and negative predictive values for cirrhosis (prevalence 11%) were 96%, 81%, 39% and 99%, respectively. For significant fibrosis (prevalence 53%), a cut-off of 7.7 kPa was 68% sensitive and 69% specific, and had a positive predictive value of 70% and a negative predictive value of 65%. Liver stiffness was independently associated with ALT, body mass index and steatosis. The optimal LSM cut-offs for cirrhosis were 11.1 kPa and 11.5 kPa in patients with ALT levels lower than 100 U/L and 100 U/L or greater, respectively. For fibrosis scores of F2 or greater, these figures were 7.0 kPa and 8.6 kPa, respectively. CONCLUSIONS: the major role of TE is the exclusion of bridging fibrosis and cirrhosis. However, TE cannot replace biopsy for the diagnosis of significant fibrosis. Because liver stiffness may be influenced by significant ALT elevation, body mass index and/or steatosis, tailored liver stiffness cut-offs may be necessary to account for these factors.

Prevalence, risk factors and causes of discordance in fibrosis staging by transient elastography and liver biopsy.

BACKGROUND AND AIMS: Liver stiffness measurement (LSM) by transient elastography (TE) is widely used for the noninvasive assessment of fibrosis. Our objectives were to examine the prevalence, risk factors and causes of discordance between fibrosis estimated by TE and liver biopsy. METHODS: Two hundred and fifty-one patients with hepatitis B, C and nonalcoholic fatty liver disease underwent LSM by TE and liver biopsy. Predictors of discordance (≥2 fibrosis stages) between measures, which occurred in 14% of patients (n=35), were identified by comparing patient, TE and biopsy characteristics of discordant and nondiscordant cases. RESULTS: According to predefined criteria, 40% of discordances were attributed to TE error and 23% to biopsy error; 37% were indeterminate. In multivariate analysis, mild fibrosis (F0-2 vs. F3-4), and higher body mass index (BMI), ALT and LSM variability [assessed by the ratio of the interquartile range to median LSM (IQR/M)] were independently associated with discordance. Discordance was three-fold more common in patients with obesity (28 vs. 9%), ALT ≥60 U/L (20 vs. 7%) and IQR/M ≥0.17 (22 vs. 7%; all P<0.005). Based on these variables, a discordance risk score assigning 1 point to each factor was developed. The prevalence of discordance in patients with 0, 1, 2 and 3 factors were 2, 7, 20, and 55% respectively (P<0.0005). CONCLUSIONS: Discordance between liver fibrosis estimated by TE and biopsy occurs in one in seven patients. In assessing the validity of TE results, clinicians must recognize risk factors for discordance and in at-risk patients, consider alternative measures including biomarkers and possibly biopsy.

Cost-effectiveness of proton-pump inhibition before endoscopy in upper gastrointestinal bleeding.

BACKGROUND & AIMS: Randomized trials suggest high-dose proton-pump inhibitors (PPIs) administered before gastroscopy in suspected upper gastrointestinal bleeding downstage bleeding ulcer stigmata. We assessed the cost-effectiveness of this approach. METHODS: A decision model compared high-dose IVPPI initiated while awaiting endoscopy with IVPPI administration on the basis of endoscopic findings. IVPPIs were given to all patients undergoing endoscopic hemostasis for 72 hours thereafter. Once the IV regimen was completed or for patients with low-risk endoscopic lesions, an oral daily PPI was given for the remainder of the time horizon (30 days after endoscopy). The unit of effectiveness was the proportion of patients without rebleeding, representing the denominator of the cost-effectiveness ratio (cost per no rebleeding). Probabilities and costs were derived from the literature and national databases. RESULTS: IVPPIs before endoscopy were both slightly more costly and effective than after gastroscopy in the U.S. and Canadian settings, with cost-effectiveness ratios of US$5048 versus $4933 and CAN$6064 versus $6025 and incremental costs of US$45,673 and CAN$19,832 to prevent one additional rebleeding episode, respectively. Sensitivity analyses showed robust results in the US In Canada, intravenous proton-pump inhibitors (IVPPIs) before endoscopy became more effective and less costly (dominant strategy) when the uncomplicated stay for high-risk patients increased above 6 days or that of low-risk patients decreased below 3 days. CONCLUSIONS: With conservative estimates and high-quality data, IVPPIs given before endoscopy are slightly more effective and costly than no administration. In Canada, this approach becomes dominant as the duration of hospitalization for high-risk ulcer patients increases or that of low-risk ulcer patients decreases.

Reduced plasma dehydroepiandrosterone sulfate levels are significantly correlated with fatigue severity in patients with primary biliary cirrhosis.

Fatigue is a common debilitating complication of primary biliary cirrhosis (PBC), the pathophysiologic mechanism of which is poorly understood. Recently, the neuroactive steroid dehydroepinadrosterone sulfate (DHEAS) was reported to be implicated in Chronic Fatigue Syndrome in the absence of liver disease. The present study was undertaken to analyse fatigue scores and their relationship with disease severity and circulating levels of DHEAS as well as its precursors DHEA and pregnenolone in PBC patients with (n=15) or without fatigue (n=10) compared to control subjects (n=11). Fatigue was assessed using the fatigue impact scale (FIS) including cognitive, physical and psychosocial subclasses. Steroids were measured by radioimmunoassay or gas chromatography/mass spectrometry. Plasma concentrations of DHEAS were significantly reduced in PBC patients with fatigue as compared to controls, while those of its precursors DHEA and pregnenolone remained within the control range. Plasma levels of DHEAS in PBC patients were significantly correlated with fatigue severity as reflected by total FIS scores including total (rp=-0.42; p=0.018), as well as the cognitive (rp=-0.37; p=0.03), physical (rp=-0.48; p=0.006) and psychosocial (rp=-0.35; p=0.04) subclasses of fatigue scores. No correlation of fatigue scores was observed with indices of liver function. These findings suggest that reduced levels of the neurosteroid DHEAS may contribute to fatigue in patients with PBC; substitutive therapy using DHEAS or its precursor DHEA could be beneficial in the management of fatigue in patients with low levels of DHEAS.

Transjugular intrahepatic portosystemic shunt before abdominal surgery in cirrhotic patients: a retrospective, comparative study.

Surgery in cirrhotic patients is associated with high morbidity and mortality related to portal hypertension and liver insufficiency. Therefore, preoperative portal decompression is a logical approach to facilitate abdominal surgery and hopefully to improve postoperative survival. The present study evaluated the clinical outcomes of 18 patients (mean age 58 years) with cirrhosis (seven alcoholics and 11 nonalcoholics) who underwent transjugular intrahepatic portosystemic shunt (TIPS) placement before antrectomy (n=5), colectomy (n=10), small-bowel resection (n=1), pancreatectomy (n=1) and nephrectomy (n=1). TIPS was performed a mean (+/-SD) of 72+/-21 days before surgery and induced a marked mean decrease in portohepatic gradient from 21.4+/-3.9 mmHg to 8.4+/-3.4 mmHg. Cirrhotic patients (n=17) who underwent elective abdominal surgery without preoperative TIPS placement were used as the control group. Both groups were matched for age, etiology of cirrhosis, indications for surgery, type of surgery and coagulation parameters. The mean Pugh score was significantly higher in the TIPS group (7.7 versus 6.2). No significant differences were observed for operative blood loss, postoperative complications, duration of hospitalization and one-month (83% versus 88%) or one-year (54% versus 63%) cumulative survival rate. Analysis using the Cox proportional hazards model showed that neither TIPS placement nor preoperative Pugh score were independent predictors for survival. The present study suggests that preoperative TIPS placement does not improve postoperative evolution after abdominal surgery in cirrhotic patients with good or moderately impaired liver function.

Increased levels of pregnenolone and its neuroactive metabolite allopregnanolone in autopsied brain tissue from cirrhotic patients who died in hepatic coma.

It has been suggested that neurosteroids with agonist properties at the central GABA-A receptor are implicated in the pathogenesis of hepatic encephalopathy (HE) in chronic liver disease. In order to address this issue, gas chromatography/mass spectrometry was used to measure the neurosteroids pregnenolone, allopregnanolone, and tetrahydrodeoxycorticosterone (THDOC) in postmortem brain tissue from controls, cirrhotic patients who died without HE, a patient who died in uremic coma, and cirrhotic patients who died in hepatic coma. Exposure of rat cerebral cortical membranes to brain extracts from hepatic coma patients resulted in a 53% (p < 0.001) increase in binding of [3H]muscimol, a GABA-A receptor ligand. Subsequent GC/MS analysis showed that concentrations of the GABA-A receptor agonist neurosteroid allopregnanolone were significantly increased in brain tissue from hepatic coma patients compared to patients without HE or controls (p < 0.001). Brain allopregnanolone concentrations were significantly correlated with the magnitude of induction of [3H]muscimol binding (r2 = 0.82, p < 0.0001). Concentrations of allopregnanolone comparable to those observed in hepatic coma brains are pathophysiologically relevant. Concentrations of the neurosteroid precursor pregnenolone were also increased in brain tissue from hepatic coma patients, while those of a second neurosteroid THDOC were below the levels of detection in all groups. Brain concentrations of benzodiazepine receptor ligands estimated by radioreceptor assay were not significantly increased in cirrhotic patients with or without hepatic coma. These findings suggest that increased levels of allopregnanolone rather than "endogenous benzodiazepines" offer a cogent explanation for the phenomenon of "increased GABAergic tone" previously proposed in HE.

[Invasive diagnosis of portal hypertension in cirrhosis: a critical evaluation of the hepatic venous pressure gradient measurement]. / Diagnostic invasif de l'hypertention portale au cours des hépatopathies chroniques. Etude critique de la mesure du gradient de pression porto-cave.

Portal hypertension is defined by an increased pressure gradient between the portal vein and the inferior vena cava (N < 5 mmHg). The most commonly used technique to assess the severity of portal hypertension is the catheterization of one hepatic vein with measurement of pressures in a free position and in a wedged position using preferably a balloon catheter. The hepatic venous pressure gradient is calculated by the difference between both pressures. In most cirrhotic processes, venous pressure gradient gives a good evaluation of portal hypertension however, portal vein pressure can be higher than wedged hepatic venous pressure, particularly in presence of an increased pre-sinusoidal resistance. In such cases, a direct access to portal vein might be needed to assess the severity of portal hypertension. For an accurate interpretation of the hepatic venous pressure gradient, several strict criteria must be followed; otherwise the validity of measurements might be seriously questioned. Hepatic venous pressure gradient has been used as a prognostic marker of portal hypertension, particularly for the occurrence of bleeding from gastrophageal varices which almost never occur below a threshold value of 12 mmHg. However, the prognostic value of the hepatic venous pressure gradient for survival is still a controversial matter On the other hand, the use of hepatic venous pressure gradient has been proposed to monitor the pharmacological treatment of portal hypertension and it is generally accepted that reaching a same threshold value of 12 mmHg should almost completely abolish the risk of first or recurrent variceal bleeding. A large number of studies have also reported that a 20% hepatic venous pressure gradient decrease should be considered as a significant response to therapy, the risk of the first or recurrent bleeding being significantly reduced in responders. But again there are conflicting results.

Increased brain concentrations of endogenous (non-benzodiazepine) GABA-A receptor ligands in human hepatic encephalopathy.

It has been suggested that alterations of GABAergic neurotransmission are implicated in the pathophysiology of hepatic encephalopathy (HE). Increased concentrations of endogenous benzodiazepines with positive allosteric modulatory properties at the GABA-A receptor complex were proposed as a pathophysiological mechanism to explain increased GABAergic tone in HE. However, results of controlled trials with benzodiazepine receptor antagonists have yielded equivocal results and increases in benzodiazepine levels in body fluids of cirrhotic patients were suggested to be largely accounted for by previous pharmaceutical benzodiazepine intake. In the present study the issue of benzodiazepine receptor ligands in brains of cirrhotic patients, and their contribution to alterations of GABA-A receptor complex in HE are addressed. "Benzodiazepine-like" ligands were present in trace amounts in autopsied brain tissue from control subjects (0.2 +/- 0.2 ng/g tissue), and from cirrhotic patients not previously exposed to benzodiazepine medication (0.8 +/- 0.4 ng/g tissue). In contrast, these ligands accumulate in brain extracts from cirrhotic patients previously exposed to benzodiazepines by up to 200-fold (161.5 +/- 93.2 DE ng/g tissue). Brain extracts from cirrhotic patients increased the binding of the GABA-A receptor agonist [3H]muscimol. This increase was minimal with brain extracts from controls (6.8 +/- 2.8%), but was significant with brain extracts from cirrhotic patients without (29.4 +/- 2.7%), or with (55.1 +/- 7.6%) previous exposure to benzodiazepines. Addition of flumazenil, a selective benzodiazepine receptor antagonist did not significantly modify the increase of [3H]muscimol binding by brain extracts from patients without prior exposure to benzodiazepines and only partially inhibited the increase of [3H]muscimol binding in presence of brain extracts from cirrhotic patients previously exposed to benzodiazepines. These findings suggest the presence of nonbenzodiazepine substances (possibly neurosteroids) with positive allosteric modulatory properties at the GABA-A receptor complex in brain in hepatic encephalopathy.